An increasing number of surgically implantable devices that function only for a relatively short period of time in vivo are being designed from synthetic polymers that are eliminated from the body by hydrolytic degradation and subsequent metabolism after serving their intended purpose. Such polymers are commonly referred to as being "bioabsorbable". For example, poly(esteramides) derived from reacting diamidediols with dicarboxylic acids, derivatives thereof, or bischloroformates are known. Such polymers and some of their uses are described in U.S. Pat. Nos. 4,343,931; 4,529,792; 4,534,349; 4,669,474; 4,719,917; 4,883,618; 5,013,315, U.S. Pat. No. 5,286,837; and U.S. application Ser. No. 07/927,447 (all Barrows et al.). Other examples of bioabsorbable polymers include polylactic acid, polyglycolic acid, polydioxanone, poly(lactide-co-glycolide), poly(trimethylene carbonate), polycaprolactone, copolymer of such polymers, or mixture of such polymers.
The use of synthetic bioabsorbable polymers in the design of new surgical devices and drug delivery implants has increased steadily since the first synthetic absorbable suture material made from polyglycolic acid was introduced in the early 1970s. The recent commercialization of polymers and copolymers of lactic and glycolic acids and the reduced regulatory burden involved with developing products made from these materials compared with products made from new synthetic materials has created a demand for novel forms of known polymers and novel fabrication techniques that extend the utility of known bioabsorbable polymers without raising new toxicological safety issues.
A bioabsorbable porous implant for healing a newly created bone void is described in U.S. Pat. No. 4,186,448 which discloses an implant with 90 percent void volume made up of randomly sized, randomly shaped, interconnecting voids. The reference teaches that such voids can be formed via a vacuum foaming process or via a process of forming connected spun filaments containing a wetting agent. The disclosed device is primarily intended for promotion of healing of the cavity or socket resulting from tooth extraction. In spite of its high porosity, the material is essentially incompressible and must be carefully cut to size prior to placement in the socket. Clinical reports of its use confirm the disadvantage of a rigid implant since the slightly oversized implants have caused patients to experience a throbbing pain after anesthesia wears off. Thus there remains a need for a porous bioabsorbable implant that is less rigid and is somewhat compressible and resilient.
Another example of a use for a porous bioabsorbable implant to maintain space and facilitate tissue regeneration is in the case of osteoarthritis of the hand where removal of the trapezium (a wrist bone) is necessary due to pain and limited range of thumb motion. It is known to use silicone rubber spacers as permanent implants, but such implants often become dislocated or lead to complications such as synovitis due to gradual breakdown of the silicone. A more preferred procedure is to fill the void with autogenous connective tissue such as a rolled-up strip of tendon. This permits a more natural healing process in which the transferred tissue can remodel into an effective soft tissue buffer between the remaining bones. A disadvantage of this approach is that it requires an additional surgical procedure to harvest the tendon graft. Another disadvantage of autogenous grafts is the possibility of excessive tissue resorption which produces a clinical result that is substantially equivalent to removal of the bone with no replacement.
Anisotropic compressibility in an implant can be highly desirable. For instance, in the case of a trapezium bone replacement as discussed above, the implant must prevent the metacarpal bone of the wrist from being displaced proximally toward the scaphoid bone of the wrist until adequate density of fibrous tissue can regenerate within the porous structure of the implant. Thus the implant is ideally less compressible in the direction corresponding to axial loading of the metacarpal bone than it is perpendicularly thereto. The biological equivalent of such an anisotropic structure is trabecular bone (also known as cancellous or spongy bone). This type of bone is very low density and provides considerable support in one direction due to the orientation of its mineralized component in such a manner that it possesses maximum strength in relationship to the vectors of the applied loads.
Another application for porous implants relates to recent advances in molecular biology that have created a supply of highly potent growth factors. Thus a porous implant can be treated with minute quantities of growth factors to provide a scaffold that induces the growth of a desired type of tissue thereby resulting in faster regeneration of a reconstructed defect. In cases where the tissue to be regenerated is bone, many different types of materials have been proposed as having an osteogenic or osteoinductive effect. These substances all require the use of a bioabsorbable scaffold or delivery vehicle for clinical utility. For example, U.S. Pat. No. 4,637,931 discloses a technique in which decalcified bone was combined with a solution of a lactide/glycolide copolymer and the solvent evaporated to produce a bone repair material. G.B. Patent Application No. 2,215,209 teaches that bone morphogenetic protein or bone derived growth factor in combination with hyaluronic acid coated on porous polylactic acid provides an effective osteogenic bone graft substitute. The enhanced healing of long bone defects also has been reported with the use of phosphophoryn calcium salt by combining it with an equal amount of collagen and freeze drying the solution to produce a porous sponge. The use of collagen, however, presents a potential risk of an immunological response to the foreign protein.
In addition to vacuum foaming and nonwoven fiber felting processes as cited above, another approach to obtaining a porous structure requires solidification of poly-L-lactide in the presence of additives such as hexamethylbenzene or parahydroxybenzoic acid followed by extraction of the additive. R.J.M. Zwiers, S. Gogolewski, and A.J. Pennings, "General Crystallization Behaviour Of Poly(L-lactic acid) PLLA: 2. Eutectic Crystallization of PLLA", Polymer, v. 24, pp. 167-74 (1983). To homogenize the polymer and the additive, prolonged heating at elevated temperature, (i.e., 10.degree. C. above the melting temperature of the highest melting component) is necessary. This temperature requirement limits the utility of this technique to only certain lower melting temperature polymers.
Another method of forming porous articles utilizing crystallization from a solution is disclosed in S. Gogolewski and A.J. Pennings, "Resorbable Materials Of Poly(L-lactide) III Porous Materials For Medical Applications", Colloid & Polymer Sci., v. 261, pp. 477-84, (1983). While these methods were shown to provide control over the pore size obtained, the difficulty in completely removing the additives was acknowledged as a serious practical problem due to their lack of biocompatibility. In many cases a large amount of the additive crystals was discovered to be firmly incorporated into the resultant polymer matrix.
Japanese Patent JP 86,146,160, according to Chemical Abstracts 105(20): 178501P, describes a sponge produced from poly-L-lactide or copolymer of lactic acid and other hydroxycarboxylic acids or lactones by dissolving in dioxane, freezing the solution, and freeze drying the resultant solid. A variation on this approach is described in Japanese Patent JP 89,104,635, according to Chemical Abstracts 111(16): 135710N, in which sucrose was added to the dioxane solution of polylactic acid prior to freeze-drying. Leaching of the resultant solid yielded a mass with a 97 percent void volume with pores between about 100 and 300 microns.
Dioxane is unique relative to other organic solvents in that it is a good solvent for polylactic acid and its freezing point of 11.8.degree. C. and boiling point of about 100.degree. to 102.degree. C. are close enough to those of water that freeze drying of dioxane solutions can be accomplished in much the same manner as freeze drying of aqueous solutions. Thus freeze drying is not a readily practical method of forming sponges if organic solvents other than dioxane are used. Dioxane, however, presents a severe disadvantage if used to process articles intended for human implantation because of its well-recognized carcinogenic properties. Similarly, the use of hexafluoroisopropyl alcohol or hexafluoroacetone sesquihydrate in the formation of polyglycolic acid sponges and foams as described in U.S. Pat. No. 3,902,497 is undesirable in view of the toxicity of those solvents.
U.S. Pat. No. 4,702,917 discloses a method of forming porous bioabsorbable polyester devices by shaping a blend of the polyester with a polyether followed by selectively eluting the polyether component to form interconnected pores in the remaining polyester mass. The method is reported to yield pores having diameters in the range of 6 to 8 microns. Pores of this size are too small for tissue ingrowth but reportedly were useful in metering high molecular weight drugs through the walls of a tube constructed of such a porous material.
The idea of treating periodontal disease with drug-releasing substances placed under the gum line at the site of infection has been of interest for many years. U.S. Pat. No. 4,568,536 describes a putty-like drug formulation for treatment of periodontal disease in which the matrix comprises a mixture of calcium stearate, dextran, and castor oil. European Patent Application No. 244,118 describes tetracycline loaded polycarbonate microparticles which gave a sustained release of drug for about 25 hours in vitro. This duration was considered adequate since it was estimated that the slow fluid exchange rate of the periodontal pocket would correspond to an in vivo release period of 10 to 20 days. Polycarbonate, however, is not bioabsorbable. Another approach described in European Patent Application No. 241,178 involves the incorporation of tetracycline in a water soluble film made with a copolymer of methacrylic acid and methyl methacrylate. U.S. Pat. No. 4,892,736 discloses a drug-releasing fiber for placement in the periodontal pocket and a retaining means such as an elastic band to keep it in place. Although "glycolic acid polymers" were also claimed, only ethylene vinyl acetate copolymer fibers were shown to produce the desired results. In addition to being too stiff for such an application, polyglycolic acid fibers could not be melt coextruded with tetracycline hydrochloride as taught in this patent without total decomposition of the tetracycline due to the high melting point of polyglycolic acid. U.S. Pat. No. 4,938,763 discloses dissolving poly-L-lactide and sanguinarine hydrochloride (Atrix Labs., Fort Collins, Colo.) in N-methyl pyrrolidinone and injecting this into the periodontal pocket where the polymer and drug coprecipitated in situ to create a bioabsorbable drug delivery implant.
An ideal implant for treating periodontal disease would be a soft, highly compressible material such as a tuft of nonwoven BMF (blown microfibers) that could be inserted into the periodontal pocket without discomfort and without easily becoming dislodged. Such a material ideally would release antibiotic for about a week and then degrade soon thereafter. Polyglycolic acid is an excellent material choice for such an application due to its rapid degradation rate and the fact that it has been used successfully in contaminated surgical sites. The disadvantages of polyglycolic acid in consideration of its use as a drug delivery vehicle, however, result from its high crystallinity, high melting point, and insolubility in all but the most toxic solvents such as hexafluoroisopropanol. Thus while the literature is replete with examples of poly-dl-lactide and lactide-co-glycolide copolymer microspheres and microcapsules for drug delivery, the literature contains no examples of pure polyglycolic acid as a matrix or carrier in the form of BMF fibers for use in drug delivery.
Similar to the periodontal disease treatment implant would be an antibiotic-releasing composition for the treatment of osteomyelitis. In this case the preferred antibiotic is gentamicin. Thin felts of BMF polyglycolic acid also could be treated with broad spectrum antibiotics and used as a prophylactic against wound infection during general closure of surgical incisions.
A BMF form of polyglycolic acid would also be useful as a better topical hemostatic material than that described in U.S. Pat. No. 3,937,223 and as a fast-absorbing reinforcement layer of a bioabsorbable film. European Patent Application No. 334,046 provides further evidence of the potential benefit of such an absorbable material in the surgical treatment of contaminated wounds.